1. Field of the Invention
The invention relates to a process for production of crystals of 11β-benzaldoxim-estra-4,9-diene derivatives, whose average particle size is in a predetermined range and whose maximum particle size does not exceed a predetermined value, to the crystals obtained thereby and to the pharmaceutical preparations containing them, especially to low-dosage preparations.
2. Description of the Related Art
EP 0 648 778 A2 discloses 11β-benzaldoxim-estra-4,9-diene derivatives. The synthesis and purification of these compounds is described in that reference. However the crystallization and shaping step is not descried in that reference. Like most steroids these compounds are crystallized from a suitable solvent. Among other things, the particle size distribution or particles sizes that arise during conventional cooling and crystallization are not disclosed.
For low dosage preparations, which contain the effective ingredient in only comparatively small amounts, for example 0.1 to 2 percent by weight, special requirements are put on the homogeneity of the active ingredient distribution (uniform content, CUT) and dissolution kinetics. In these low dosage preparations the active ingredient present in very limited amounts is diluted with the other medicinal ingredients to a considerable extent. A certain average particle size should not be exceeded and the scatter or spread of the distribution should not be too great, so that the uniformity of the effective ingredient distribution remains nearly constant. This maximum particle size depends on the dosage and the application form and can be determined statistically. Furthermore with low dosage formulations the fact that smaller particles dissolve more rapidly in the stomach than larger particles must be considered. A certain particle size must not be exceeded in order to meet the requirement in regard to dissolution kinetics.
Currently crystallizates are micronized in a jet mill according to traditional engineering to obtain the required uniformity of effective-ingredient distribution and dissolution kinetics, especially for low-dosage preparations. Average grain sizes of from 1.5 to 3 μm are obtained. An enormous increase in surface area as well as a thermodynamic activation of the surface occurs by partial amorphization and/or by considerable destruction or perturbation of lattice structure. These physical changes cause a considerable chemical destabilization of the effective ingredient not only in its pure form, but also and above all, when it is present in a pharmaceutical preparation.
The carbamate functional group of the above-mentioned 11β-benz-aldoxim-estra-4,9-diene derivative decomposes to form a nitrile by splitting off ethylamine and CO2. The use of a micronizate thus leads to medicinal preparations, in which the effective ingredient is not sufficiently stable under ICH, i.e. (40° C., 70% relative humidity).
Lowering the milling pressure of course leads to a slight increase in the average particle size, but also to an undesirable increase in its spread. However a certain minimum pressure is absolutely required for operation of the mill. It has currently been possible to use the form of the solid to obtain better chemical stability through the micronization parameters to an only very limited extent.